Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study

3006 Background: FORE8394 is an investigational inhibitor (i) of class 1 (V600) and 2 (activating non-V600) BRAF-altered tumors. FORE8394 did not have paradoxical activation of the MAPK pathway in nonclinical studies. Methods: In a phase 1/2a study, patients (pts) aged ≥3 years with BRAF-altered, advanced solid or CNS tumors received FORE8394 (900-3600 mg/day or mg/m 2 dosing) with or without a pharmacokinetic booster (cobicistat 150 mg/day). CNS metastases and prior treatment with other BRAFi were allowed. Besides standard safety assessments, skin and eye exams were required. Objective response was assessed by RECIST v1.1 or RANO criteria. Efficacy was evaluated in pts with class 1/2 BRAF alterations and ≥1 post-baseline assessment, with mg/m 2 dosing (n=4) reported separately. Results: On 21Nov2022, 110 pts had received ≥1 dose of FORE8394. 85% completed ≥1 4-week cycle. 10 (9%) and 3 (3%) received FORE8394 ≥2 and ≥6 years, respectively; 14 (13%) are ongoing. Pts included 61 (55%) class 1 mutations, 19 (17%) class 2 mutations (excluding fusions), and 17 (15%) BRAF fusions. 64 pts (58%) had ≥2 prior lines of systemic therapy; 28 (25%) received prior MAPKi. Increased ALT (39%), increased AST (35%), fatigue (34%), nausea (27%), diarrhea (22%), and vomiting (20%) were the most frequently reported treatment-emergent adverse events (TEAEs); most were grade (G) 1/2. G3+ TEAEs were reported in 49% (54/110), the most common being increased ALT (9%), increased blood bilirubin (6%), and hyponatremia (5%). Transient G1 pyrexia was observed in 8 (7%) pts. All rashes were G1; none required a dose change. No TEAE of hyperkeratosis, papilloma, uveitis, retinal detachment, or LVEF reduction were reported. 1 pt discontinued due to FORE8394-related TEAE. Antitumor activity was observed in pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]), 39% (9/23) having a PR (median duration of response [DoR]: 32 months). In 17 pts with V600 mutated tumors (excluding CRC) treated with prior MAPKi, 3 (18%) had PR and 5 (29%) had SD. In V600 mutated tumors, PRs occurred in 6 (55%) gliomas, 3 (100%) ovarian cancers, and 1 each in CRC (7%), small bowel (50%), papillary thyroid (13%) and anaplastic thyroid (25%) cancers. Of pts with BRAF-fusions, a pt with AGK-BRAF-fused melanoma had CR (DoR 51.8+ months); 46% (6/13) had SD. Of note, 1 child with V600E mutated Langerhans cell histiocytosis had SD with improvement in neurodegenerative changes and a progression-free survival of 55.8+ months. Conclusions: As single agent anticancer therapy, FORE8394 had antitumor activity in various tumors with BRAF alterations, including pts previously treated with MAPKi and pts with BRAF fusions. Durable tolerability was observed, and TEAEs indicative of paradoxical MAPK activation were not observed, consistent with the novel mechanism of action of FORE8394. These results support further evaluation of FORE8394. Clinical trial information: NCT02428712

Dose optimization of novel BRAF inhibitor FORE8394 based on PK and efficacy results

3106 Background: FORE8394 is a selective inhibitor of class 1 (V600) and 2 (activating non-V600) BRAF alterations that avoids paradoxical MAPK pathway activation. Consistent with the paradigm shift to optimal dosing vs identifying the maximal tolerated dose, integrated pharmacokinetic (PK), genomics, safety, and efficacy data, and exposure-response modeling were used to identify the recommended dose (RD). Methods: In a single arm phase 1/2a study, patients (pts) age ≥3 years with advanced solid or CNS tumors with BRAF alterations received FORE8394 900-3600 mg/day with or without the PK enhancer cobicistat (cobi) until progression. Efficacy pts had class 1 or 2 BRAF alterations & ≥1 post-baseline assessment (mITT); the BRAF V600 MAPKi naïve, non CRC subset provided a homogenous subset to also inform dose selection. PK was evaluated after single and repeated dosing. Results: To date, 110 pts (age range 4-86 years) received ≥1 dose of FORE8394; 58% had ≥2 prior lines of therapy, 25% had prior MAPKi. PK was independent of age or weight. Cobi increased FORE8394 exposure 2-3-fold. Exposure increased with dose, with less than proportional increase at doses >900 mg BID. Higher Cmax and trough levels were achieved with QD vs BID/TID. Objective (confirmed) responses were observed at all doses; however, objective response rate (ORR) was greatest (50%) at 900mg QD + cobi, with no further increases in ORR at higher doses. Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). Similarly, treatment-emergent adverse events (TEAEs) ≥Grade 3 (G3) increased at the higher doses. Only 1 pt discontinued FORE8394 due to treatment-related AE (G3 bilirubin; 3600 mg/day). Conclusions: Based on the entirety of safety, PK, and efficacy data, the optimal RD of FORE8394 in Phase 2 is 900 mg QD + cobi in pts ≥10 years old. This achieved targeted efficacious exposures with robust antitumor activity and favorable safety. This dose optimization is consistent with current guidelines, avoids higher exposure that may lead to higher toxicity and compromise dose intensity. QD dosing also allows for a convenient dosing regimen. A Phase 2 study at the RD is ongoing in pts with recurrent V600E BRAF-mutated primary CNS tumors and advanced solid or CNS tumors with BRAF fusions. Clinical trial information: NCT02428712 . [Table: see text

International multicenter study comparing COVID-19 in patients with cancer to patients without cancer: Impact of risk factors and treatment modalities on survivorship

International audienceBackground: In this international multicenter study, we aimed to determine the independent risk factors associated with increased 30 day mortality and the impact of cancer and novel treatment modalities in a large group of patients with and without cancer with COVID-19 from multiple countries. Methods: We retrospectively collected de-identified data on a cohort of patients with and without cancer diagnosed with COVID-19 between January and November 2020 from 16 international centers. Results: We analyzed 3966 COVID-19 confirmed patients, 1115 with cancer and 2851 without cancer patients. Patients with cancer were more likely to be pancytopenic and have a smoking history, pulmonary disorders, hypertension, diabetes mellitus, and corticosteroid use in the preceding 2 wk (p≤0.01). In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin, and procalcitonin) but were less likely to present with clinical symptoms (p≤0.01). By country-adjusted multivariable logistic regression analyses, cancer was not found to be an independent risk factor for 30 day mortality (p=0.18), whereas lymphopenia was independently associated with increased mortality in all patients and in patients with cancer. Older age (≥65y) was the strongest predictor of 30 day mortality in all patients (OR = 4.47, p<0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30 day mortality (OR = 0.64, p=0.036). Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30 day mortality rate than those who did not (5.9 vs 17.6%; p=0.03). Conclusions: Increased 30 day all-cause mortality from COVID-19 was not independently associated with cancer but was independently associated with lymphopenia often observed in hematolgic malignancy. Remdesivir, particularly in patients with cancer receiving low-flow oxygen, can reduce 30 day all-cause mortality